PurposeLumefantrine is a key partner drug in artemether-lumefantrine therapy, yet data describing its pharmacokinetics among women with efavirenz-based antiretroviral therapy remains limited. This study aimed to characterise the population pharmacokinetics of lumefantrine in pregnant and non-pregnant Nigerians living with HIV, evaluate the influence of pregnancy and CYP3A5 genotype, and assess the adequacy of current and alternative dosing regimens with respect to day-7 plasma concentration targets.MethodsPlasma lumefantrine concentrations were analysed using nonlinear mixed-effects modelling in Pumas. Structural models comprising one to three compartments, along with alternative absorption models, were evaluated. Pregnancy status and CYP3A5 expressor status, among other candidate covariates, were tested using a stepwise covariate modelling procedure. Model robustness was assessed using nonparametric bootstrap resampling and simulation-based diagnostics. Monte Carlo simulations were then performed to compare the probability of achieving a day-7 lumefantrine concentration of at least 0.2 µg/mL under current versus alternative dosing regimens.ResultsLumefantrine pharmacokinetics were adequately described by a two-compartment model with transit absorption. Pregnancy status and functionally relevant CYP3A5 genotype were not identified as significant covariates on lumefantrine pharmacokinetic parameters among the study population. At the currently recommended twice-daily dosing for 3 days, approximately 65% of simulated patients achieved the day-7 concentration target. Extending dosing to twice daily for 5 days increased target attainment to approximately 96%, while alternative intensified regimens also improved exposure.ConclusionsNo statistically significant effect of pregnancy on lumefantrine pharmacokinetics was identified in this EFV-treated population. However, the standard 3-day dosing regimen may result in suboptimal exposure in a substantial proportion of patients. Simulation results suggest that extended dosing regimens could markedly improve day-7 target attainment, supporting further evaluation of alternative dosing strategies to optimise the efficacy of artemether-lumefantrine among people with concurrent EFV-based ART.